Immunologic signatures of nontuberculous mycobacterial pulmonary disease

Nontuberculous mycobacteria (NTM) can cause chronic infection in humans, with pulmonary disease (PD) being the most common manifestation. In this study, we used digital spatial profiling techniques on lung tissue from patients undergoing surgical resection for NTM-PD and non-NTM bronchiectasis to analyse the immunological signatures of NTM-PD. We performed whole transcriptomic analysis of immune cells (CD3+ and CD68+ cells) in peribronchial regions of 6 patients with NTM-PD and 4 patients with non-NTM bronchiectasis who underwent surgical resection at Seoul National University Hospital between January 2006 and December 2020. Transcriptomic findings were validated by immunohistochemistry using surgical specimens obtained from 45 patients with NTM-PD and 15 patients with non-NTM bronchiectasis. A total of 30 regions of interest were analysed. In the peribronchial regions, 766 genes were upregulated in NTM-PD, while 524 genes were downregulated. NTM-PD showed upregulation of genes associated with antigen processing and presentation, T cell-mediated cytotoxicity and cellular responses to type II interferon. These pathways were also upregulated in macrophages, but not in T cells. In addition, genes associated with effector function, such as CASP3 or GZMB, were downregulated in T cells, whereas HAVCR2 and LILRB4 genes, which regulate immune response, were upregulated. Consistent with the transcriptomic analysis, in a validation study, the expression of CD86 and CD163 was increased in NTM-PD macrophages. In NTM-PD T cells, the expression of TIM3 was increased, whereas granzyme B was suppressed. In conclusion, pro-inflammatory responses are upregulated in macrophages but not in T cells in NTM-PD.